α-Alkyl-α-amino acids represented by the formula H2NCH(R)COOH are very important naturally-occurring α-amino acids. α-Alkyl-α-amino acids in which the α-carbon has the L-configuration are a structural component of proteins (polypeptide chains) that exist in animals, plants, and microorganisms, for example. The D-form of α-alkyl-α-amino acids exists in plants, fungi and microorganisms as a structural component of non-proteogenic compounds. On the other hand, α,α-dialkyl-α-amino acids are recently gaining attention because of their unique functions, including the fact that they are stereochemically stable and that when they are incorporated into peptides, those peptides are not susceptible to enzymatic hydrolysis by proteases (see Bellier, B. et al. (1997). J. Med. Chem. 40:3947 and Mossel, E. et al. (1997). Tetrahedron Asymmetry 8:1305). These properties have led α,α-dialkyl-α-amino acids to be considered for use as chiral building blocks for the synthesis of peptides having enhanced activity, effective enzyme inhibitors, and compounds having other biological activities. Methods for synthesizing non-proteogenic α-amino acids, particularly α,α-dialkyl-α-amino acids, by selectively building the stereochemistry of the α-carbon have been investigated, but at the present time, a practical method has not yet been found.
Chiral phase-transfer catalysts allow stereoselective alkylation of glycine derivatives and are easy to use and can be applied widely, and thus have become increasingly important in the field of process chemistry. A large number of researches into designing phase-transfer catalysts have been conducted mainly by using cinchona alkaloid derivatives, and to date several useful methods have been reported (e.g., see Shioiri, T. et al., Stimulating Concepts in Chemistry, edited by Vogtle, F. et al., WILEY-VCH: Weinheim, p. 123, 2000; and O'Donnell, M. J. (2001). Aldrichimica Acta, 34:3). However, when such phase-transfer catalysts are used, various problems are caused, including the fact that halogen-based solvents are employed, the reaction is sluggish, and low temperature conditions are required. In particular, the use of chiral phase-transfer catalysts derived from such cinchona alkaloids is not particularly efficient in the synthesis of α,α-dialkyl-α-amino acids.
The present inventors have prepared an optically active quaternary ammonium salt having axial asymmetry, and have clearly shown that it can be used as a phase-transfer catalyst for stereoselectively synthesizing α-alkyl-α-amino acids and α,α-dialkyl-α-amino acids (see Japanese Laid-Open Patent Publication No. 2001-48866; Japanese Laid-Open Patent Publication No. 2003-81976; and Ooi, T. et al. (2000). J. Am. Chem. Soc. 122:5228). For example, a spiro-compound represented by the following formula is very effective for stereoselectively producing α,α-dialkyl-α-amino acids because it catalyzes the stereoselective double alkylation of glycine derivatives and the stereoselective monoalkylation α-alkyl-α-amino acid derivatives:
(where PhF3 represents a 3,4,5-trifluorophenyl group). However, the preparation of such spiro-type catalysts requires many steps, and for example, if chiral binaphthol, which is easily available, is used as the starting raw material, then eleven process steps are required just to prepare the left half of this catalyst structure. Therefore, drawbacks of conventional optically active quaternary ammonium salts having axial asymmetry are extremely time-consuming and costly nature of their preparation.